Mesenchymal stromal cells (MSCs), designated mesenchymal stem cells by some investigators, hold promise for the future therapy of diseases in nearly all tissues in the body. This application addresses Thematic Area 2, "Translating Basic Science Discoveries into New and Better Treatments," by building on three critical observations in our MSC research. (i) We previously demonstrated that the intravenous infusion of ex vivo- expanded MSCs unequivocally (but transiently) stimulates growth in children with severe osteogenesis imperfecta (OI), a genetic disorder of bone in which the characteristic growth deficiency has no proven effective therapy. (ii) In contrast to the much current opinion that MSCs are immune privileged, our clinical trial data suggest that MSCs may be recognized by host immune effector cells. (iii) We recently showed in a murine model that a soluble protein released by ex vivo-expanded MSCs mediates the growth-promoting activity of these primitive stromal cells. Thus, we hypothesize that repeated infusions of MSCs, by providing constant stimulation of growth-promoting activity, could maintain normal or near-normal growth rates in children with OI. In this application, we propose to test our hypothesis by conducting a clinical trial, approved by both the FDA and our IRB, in which we will intravenously infuse allogeneic MSCs into children with severe OI every 4 months for 2 years. In Aim 1, we will assess the clinical safety of repeated infusions of MSCs, while Aim 2 addresses the critical question of allogeneic MSC immunogenicity by undertaking a complete analysis of humoral and cell-mediated immune responses in fully immune competent patients receiving repeated infusions of MSCs without prior bone marrow transplantation. Demonstration of allo-reactivity in this phase of the trial would have broad implications for the continued use of allogeneic MSCs in regenerative medicine trials worldwide. Aim 3 will assess the clinical outcome of repeated infusions of MSCs in patients with severe OI, through measurements of linear growth, bone mineralization, developmental progress, and quality of life. The strengths of this proposal are the applicant's extensive track record of laboratory-based clinical trials of bone marrow cell therapy for OI, the secured regulatory approvals assuring feasibility and readiness for immediate implementation, the potential to demonstrate a novel therapy for a presently incurable pediatric disease, and the unique opportunity to prospectively evaluate the allo-immunogenicity of MSCs in immune competent patients. The data generated in this 3-year project will provide the foundation for the next generation of MSC clinical trials, not only for children with OI, but extending potentially to other disorders of bone, including osteoporosis, as well as any disorder targeted by MSC research. PUBLIC HEALTH RELEVANCE: The objective of the proposed clinical trial is to develop a novel mesenchymal stromal cell (MSC) therapy to stimulate a durable accelerated growth velocity in children with severe osteogenesis imperfecta (OI), a genetic disorder of bone in which marked growth deficiency is a cardinal manifestation. This therapeutic opportunity will enable us to prospectively evaluate the immunogenicity of allogeneic MSCs, which will not only directly benefit children with OI, but have broad ramifications for MSC research in all disorders. Thus, the outcome of this translational research will substantially impact the direction of the next generation of MSC clinical trials.